11beta, 18, 18, 20-diepoxy steroids of the pregnane series



B are typified by the following:

United States Patent 3,216,998 115,18,18,20-D[EPOXY STEROIDS OF THEPREGNANE SERIES Philip F. Beal III and John E. Pike, Kalamazoo, Mich.,assignors to The Upjohn Company, Kalamazoo, MiclL,

a corporation of Delaware No Drawing. Filed Apr. 2, 1964, 'Ser. No.356,945 21 Claims. (CL 260-239.55)

This invention relates to certain novel and therapeutically useful11fi,l8;l8,20B-diepoxy and 11,8,18;18,20adiepoxy steroids of thepregnane series.

This application is a continuation-in-part of copending applicationSerial No. 25,824, filed May 2, 1960.

The novel compounds of this invention are illustratively represented bythe following formulae:

wherein R is hydrogen, hydroxy or OAc in which Ac is the acyl radical ofan organic carboxylic acid preferably a hydrocarbon carboxylic acidcontaining from 1 to 12 carbon atoms, inclusive, X is the carbonylradical C:O) or the ,B-hydroxymethylene radical X is the carbonylradical C:O), the hydroxymethylene radical or an acylatedhydroxymethylene radical in which Ac has the same meaning as givenabove, the 1,2-carbon atom linkage is a single bond linkage or a doublebond linkage, and the configuration of the carbon to oxygen linkage atthe 20-position is a (alpha) or B (beta).

In this application the wavy line (2) appearing at the 3-, 5- and20-positions is a generic expression consisting of the 0: (alpha)configuration, the [3 (beta) configuration, and mixtures thereof.

The compounds of this invention represented by Formulae A and B, above,are highly potent cortical hor- ,mones having salt and water regulating,anti-inflamma tory, progestational, central nervous system depressant,muscle relaxant, cardiotonic, anti-hypertensive and antihormonalactivities; the compounds of Formulae A and 1 B, ;1 B- diepoxy 5 3pregnan 3a o1, 115,18;18,20fl diepoxy- 5,8 pregnane 3u,2l diol,l1fl,18;18,20,3 diepoxy- 5B pregnan 3 one, llfl,l8;18,20,8 diepoxy 21-hydroxy 5B pregnan 3 one, 1lfi,l8;18,20a diepoxy- 55 pregnan 3a o1,11B,l8;18,20oz diepoxy 5,6- pregnane 30:,21 diol, 11B,18;l8,20a diepoxy5B- pregnan 3 one, llfi,l8;l8,20a diepoxy 21 hydroxyice 5,8 pregnan 3one, the acylates thereof, and the corresponding 35,511 epimers; and (B)1lfi,18;18,20fidiepoxy 4 pregnen 3 one, llfi,18;l8,20/3 diepoxy- 21hydroxy 4 pregnen 3 one, 1l 3,18;l8,20adiepoXy 4 pregnen 3 one,1l;3,18;18,20a diepoxy- 21 hydroxy 4 pregnen 3 one, the correspondingl-dehydro compounds and the 2l-acylates of the 21-hydroxy compounds.

Other compounds of this invention, as well as being useful asintermediates in the production of the above described compounds, alsopossess useful physiological activities, including salt and waterregulating, anti-inflammatory, progestational, central nervous systemdepressant, cardiotonic and antihormonal activities. Among these are thecompounds represented by Formulae XVI, XVII and XVHI.

The novel compounds of this invention can be prepared and administeredto birds and mammals, including valuable domestic animals, in a widevariety of oral or parenteral dosage forms singly, or in admixture withother coacting compounds. They can be associated with a pharmaceuticalcarrier which can be a solid material or a liquid in which the compoundis dissolved, dispersed or suspended. The solid compositions can takethe forms of tablets, powders, capsules, pills or the like, preferablyin unit dosage forms for simple administration or precise dosages. Theliquid compositions can take the form of solutions, emulsions,suspensions, syrups or elixirs. The novel compounds can also beadministered topically in the form of ointments, creams, lotions, andthe like, with or without coacting antibiotics, germicides or other materials forming advantageous compositions therewith.

The compounds and processes of this invention are illustrativelyrepresented by the following sequence of for- .mulae.

C'HQOAc 0 Iran on, on on, n 5 I n O\('3HaR' 0 11211" 61, CH (12 CH 15H07 1 0H CH2! or (VIII) H (III) H H 0 :H2R' /O\(|3HzR o-c H on 01-1, onCH5] on A. OW A Q/w c c t (1X) O\CH;R o c112ru' 0(II dn 0 1 (in IA IAoni on HOW (XI) 0- (XII) H H l 0 onioac O\(|3H2R O.-C/H 211 0-61 on i \lon] 0111 (XIII) (XIV) H CmR' 0 on, I

C/fliigm. WA CHI j (XVI) (VII) o JH,n 0 (IJHZR (H, CH o In c11 H0 IHO-fil on on;

0 (XVII) (XIX) o CHQR 0 omit o 11%11 O-CH on IA on; i on 0 (XVIII) (XIVwherein Ac and R have the same meanings as previously given, R' ishydrogen or OAc in which Ac has the same meaning as previously given, R"is hydrogen or hydroxy, Z is a lower alkylene radical containing from 2to 8 carbon atoms, inclusive, and from 2 to 3 carbon atoms, inclusive,in the chain connecting the oxygen atoms, e.g., ethylene, trimethylene,2,2-dimethyltrimethylene, n-propyl-ethylene, 1,1,2,2-tetramethylethyleneand the configuration of the carbon to oxygen linkage at the 20-positionis 0: (alpha) orfi (beta).

Starting materials for this invention are3a,20/8-dihydroxy-Sfl-pregnan-ll-one 3-acylate (I),3,3,20,8-dihydroxy-Sa-pregnan-ll-one 3-acylate (I),3a,20[3,21-trihydroxy-Sfi-pregnan-ll-one 3,2l-diacylate (I), 3 8,205,21-tIihydIOXy-Sa-pregnan-Il-one 3,21-diacylate (I), 30:,11 3, 208-trihydroXy-5/8-pregnane 3-acylate, 33,11fi,20fl-trihydroxy-ia-pregnane 3-acylate,3a,115,205,21-tetrahydroxy- 5,8-pregnane 3,21-diacylate,35,11B,20fi,21-tetrahydroxy- Saregnane 3,21-diacylate,20,8-hydroxy-4-pregnene-3, ll-dione 3-alkylene ketal (XV),2018,21-dihydroxy-4-pregnene-3,11-dione 3-alkylene ketal 21-acylate(XV), 115, 20 8-dihydroXy-4-pregnen-3-one 3-alkylene ketal and 11,8,205,21-trihydroxy-4-pregnen-3-one 3-alkylene ketal 21- acylate, and thecorresponding ZOu-epirners thereof, wherein acyl is the acyl radical ofan organic carboxylic acid preferably a hydrocarbon carboxylic acidcontaining from 1 to 12 carbon atoms, inclusive, and wherein thealkylene radical contains from 2 to 8 carbon atoms, inclusive, and from2 to 3 carbon atoms, inclusive, in the chain connecting the oxygenatoms. The compounds: wherein the acyl radical is acetyl and wherein thealkylene group is ethylene are the preferred starting materials.

The above listed starting materials are prepared by subjecting thecorresponding 20-keto compounds which are known in the art to reductionat the 20-position using sodium borohydride as the reducing agent inaccordance with known methods, e.g., Oliveto et al., I. Am. Chem. Soc.,75, 488-490 (1953), as shown in Preparation 1, contained herein.

ROUTE 1 In carrying out the process of Route 1 of this invention, thecompounds of Formula I, i.e., 3a,20,8-dihydroxy- 5B-pregnan-11-one3-acylate, 3u,20,B,21-trihydroxy-5{3- pregnan-l l-one 3,21-diacylate orthe corresponding 3,8, 5u-epimers are epoxidized with lead tetraacetatein the presence of a suitable solvent inert to the reaction such asbenzene, toluene, xylene, hexane, cyclohexane, methylcyclohexane and thelike at a temperature of from about 0 C. to the boiling temperature ofthe solvent, to give the corresponding 18,20/3-epoxy compounds (II). Thecompounds of Formula II are then hydrolyzed with base in accordance withknown methods, e.g., dilute alcoholic sodium or potassium hydroxidesolution, to produce the corresponding free hydroxy compounds of FormulaIII. The compounds of Formula III thus produced, can be re-esterified tothe corresponding 3-acylates and 3,21- diacylates, respectively, ofFormula II by reaction with the selected acylating agent. This reactioncan be performed under the esterification conditions known in the art,e.g., by the reaction of III with the selected acid chloride or acidbromide or the anhydride of an organic carboxylic acid, or by reactionwith the selected acid in the presence of an esterification catalyst,for example, ptoluenesulfonyl chloride, trifiuoroacetic anhydride,p-toluenesulfonic acid, trifiuoroacetic acid, sulfuric acid, and thelike, or with an ester under ester exchange reaction conditions.Compounds thus produced include those wherein Ac is the acyl radical ofa hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms,inclusive, e.g., the acids listed in Example 3.

The compounds of Formula II or the corresponding free hydroxy compoundsof Formula III are reduced at the ll-position with lithium aluminumhydride or other carbonyl reducing agent in an organic solvent ormixtures of organic solvents, e.g., ether, dioxane, tetrahydrofuran,benzene, toluene and the like, to produce the corresponding18,20fi-epoxy-llfi-hydroxy compounds of Formula VIII. When the startingmaterial is a 3-acylate or 3,21- diacylate (III) the acylate group isremoved during the reaction to give the corresponding free hydroxycompound VIII, which can be re-esterfied to give the corresponding3-acylate and 3,21-diacylate (IX), respectively, by the known acylationmethods, e.g., those disclosed above for converting III to II.

The 18,20/3-epoxy-11fi-hydroxy compounds of Formula 1X are thenepoxidized with lead tetraacetate in the presence of a suitable solventsuch as benzene, toluene, xylene, hexane, cyclohexane, methylcyclohexaneand the like, at a temperature from about 0 C. to the boiling point ofthe solvent to give the 11,8,18;18,20;3-diepoxy compounds of Formula X.

Alternatively the compounds of Formula X can be prepared from3a,l1B,ZOfi-trihydroxy-5/8-pregnan-3-one 3-acylate, 3c,115,20521-tetrahydroxy-5,8-pregnan-3-one 3,2l-diacylate or thecorresponding 35,5a-epimers thereof by diepoxidation with leadtetraacetate in accordance with the procedure disclosed above forepoxidation of IX to X, but using an appropriately increased amount oflead tetraacetate.

The 11fl,l8;l8,20B-diepoxy compounds of Formula X are then hydrolyzed tothe corresponding free alcohols of Formula XI in accordance with theprocedures previously disclosed for hydrolyzing II to III.

The 3u-hydroxy-18,2OB-epoxy-5B-pregnan-1l-one (III),3a-hydroxy-11,8,18;18,ZOB-diepoxy-Sfi-pregnane (XI) and thecorresponding 3B,5u-epimers are oxidized at the 3- position by knownmethods, e.g., with an N-haloamide or an N-haloimide in pyridine, withchromic anhydn'de or chromium trioxide and dilute sulfuric acid inacetone or methylene chloride, with sodium dichrornate in glacial 6acetic acid, or other known oxidizing agents to produce thecorresponding 3-keto compounds of Formula IV and XII.

The 3,21-dihydroxy compounds of Formulae III and X are oxidized at the3-position (Oppenauer oxidation) with a ketone, e.g., acetone orcyclohexanone, in the presence of aluminum isopropoxide, to give thecorresponding 3- keto-Zl-hydroxy compounds of Formula IV and XII, whichcan be acylated at the 21-position in accordance with known Zl-acylationmethods, e.g., the procedures disclosed above for acylating III to II togive the corresponding 21-acylates represented by Formula V and XIII.

The 3-keto compounds of Formula IV can be. converted to thecorresponding llfl-hydroxy compounds of Formula VI by ketalizing the3-position with an alkylene glycol according to the method of US. Patent2,707,184 or 2,758,993 or with the acetal of a lower-alkylene glycol,e.g., dioxolane, 2-methyl-2-ethyldioxolane, in the presence of an acidcatalyst, e.g., p-toluenesulfonic acid, concentrated sulfuric acid,boron trifluon'de, etc., to produce the corresponding 3-cyclic ketals.Ethylene glycol is the preferred ketalizing agent.

The 3-ketalized compounds of Formula IV, thus produced, are then reducedat the ll-position with lithium aluminum hydride or other carbonylreducing agent in an organic solvent or mixtures of organic solvents,e.g., ether, dioxane, tetrahydrofuran, benzene, toluene, and the like,to produce the corresponding 3-ketali'zed ILB-hydroxy compounds whichare then hydrolyzed by known methods for hydrolyzing cyclic ketalgroups, e.g., dilute sulfuric acid, according to the method of US.Patents 2,707,- 184 or 2,758,993 for hydrolyzing 3-cyclic ketals, togive the compounds of Formula VI. The 21-acyloxy compounds of Formula V,can likewise be ketalized and reduced to give the corresponding21-hydroxy compounds of Formula VI.

The 21-hydroxy compounds of Formula VI can be esterified at the21-position in accordance with known 21- acylation methods, e.g., theprocedures disclosed above for the acylation of III to II to give thecorresponding 21 acylates represented by Formula VI.

The 21-desoxy-5fi-pregnanes of Formulae IV and XII and the21-acy1oxy-5l3-pregnanes of Formulae V and XIII, i.e.,18,20fi-epoxy-5fl-pregnane-3Jl-dione (IV),11,8,18;18,205-diepoxy-5B-pregnan-3-one (XII), 18,20,9- epoxy-2l-hydroxy-SB-pregnane-S,1l-dione 21-acetate (V) and 11B,18;18,20fl-diepoxy-21-hydroxy-5fl-pregnan-3-one 21-acy1ate (XIH) arethen treated with a halogenating agent, e.g., a hypohalous acid, amineral acid with a hypochlorite, such as t-butylhypochlon'te,N-bromoacetamide, N-bromosuccinimide, N-chloroacetamide,N-chlorosuccinimide and the like, to give the corresponding 4,3-halo-18,ZOfi-epoxy-5/3-pregnane-3,1l-dione, the corresponding 4,6halo-l1B,l8;18,20,8-diepoxy-5/i-pregnane-3-one, the corresponding4,8-halo-18,20,8-epoXy-2l-hydroxy-Sfi-pregname-3,1 l-dione ZI-acyl'ateand the corresponding 4,B-halo- 1l/3,18;18,20B-diepoxy-5fl-pregnan-3-one2-acylate, respectively. The 4-halo compound thus obtained can beconverted to the corresponding A compound according to the proceduresdisclosed in US. Patent 2,794,814, e.g., by treatment with semicarbazidehydrochloride followed by pyruvic acid, to give the corresponding A-compounds of Formulae VII and XIV, i.e., 18,20fi-epoxy-4-pregnene-3,11-dione (VII), 113,18;18,20f3-diepoxy-4-pregnen-3- one (XIV),18,20B-epoxy-2l-hydroxy-4-pregnene-3,11-dione 21-acylate (VII) and11,8,18;18,20fl-diepoxy-2l-hydroxy-4-pregnen-3-one 21-acylate (XIV),respectively.

The 3-keto-5a-pregnanes of Formulae IV, V, KB and XIII are converted tothe corresponding A -compounds of Formulae VII and XIV by methods knownin the art, Rosenkranz et al., J. Am. Chem. Soc., 72, 4077 (1950), e.g.,by bromination of the selected 3-keto-5a-pregnaue to give thecorresponding 20,4cz-dibIOII1O derivative followed by reaction withsodium iodide to give the corresponding 2-iodo-4-pregnene which ondeiodination with 21 dihydroxy-l 8,20/8-epoxy-4-pregnen-3 -one 7 chromuschloride, collidine or zinc dust gives the corresponding A -,3-ketnes ofFormulae VII and XIV.

ROUTE 2 In carrying out the process of Route 2 of this invention, thecompounds of Formula XV, i.e., 20,8-hydroxy-4-pregnene-3,11-dione3-alkylene ketal and 20,8,21-dihydroxy- 4-pregnene-3,l1-dione 3-alkyleneketal Zl-acylate, are epoxidized with lead tetraacetate in accordancewith the procedures disclosed above for converting I to II to give thecorresponding 18,20fl-epoxy compounds of Formula XVI, i.e.,18,20B-epoxy-4-pregnene-3,1l-dione 3-alkylene ketal and18,20,8-epoxy-21-hydroxy-4-pregnene-3,1l-dione 3-alkylene ketal21-acylate, respectively. The 2l-acylates thus obtained are thenhydrolyzed in accordance with known methods for hydrolyzinghydrocortisone 21-acylates to hydrocortisone, e.g., sodium or potassiumbicarbonate in aqueous alcohol in an oxygen free atmosphere to give thecorresponding 18,20,8-epoxy-21-hydroxy-4- pregnene-3,ll-dione S-alkyleneketal (XVI).

The compounds of Formula XVI are then reduced at the ll-position withlithium aluminum hydride or other carbonyl reducing agent in the samemanner as disclosed in Route 1, above, to produce the correspondingllfl-hydroxy compounds of Formula XVII, i.e., llfi-hydroxy-lS,20fi-epoxy-4-pregnen-3-one 3-alkylene ketal and 11 3,21-dihydroXy-l8,20fl-epoxy-4-pregnen-3-one 3-alkylene ketal. When thestarting material is the 21-acylate, the acyloxy group is hydrolyzedduring the course of the reaction to give the corresponding 2l-freealcohol (XVII). The 21- free. alcohols of Formula XVII, thus obtained,are esteri- 'fied at the 21position in accordance with known acylationprocedures, e.g., those disclosed above for converting 'III to II, togive the corresponding 21-acylates represented 'by Formula XVII.

The compounds of Formula XVII, i.e., llfl-hydroxy-18,20,6-epoxy-4-pregnen-3-one 3-alkylene ketal and 11p, 3-alkylene ketal2l-acylate, the acetates being preferred, are epoxi- 'dized with leadtetraacetate in accordance with the procedure disclosed above forconverting IX to X, to give the corresponding diepoxy compounds ofFormula XVIII, i.e., 11p,18;18,20,e diepoxy-4-pregnen-3-one 3-alkyleneketal and 11,8,18;18,20p-diepoxy-4-pregnen-3-one 3-alkyl- 'ene ketal21-acylate, respectively.

Alternatively the 21-desoxy and 21-acyloxy compounds of Formula XVIH canbe produced by the diepoxidation of 1113,205-dihydroxy-4-pregnen-3-one3-alkylene ketal and 115,2053l-trihydroxy-4-pregnen-3-one 3-alkyleneketal 2l-acy1ate with lead tetraacetate in accordance with thealternative procedure described in Route 1 for producing the compoundsof Formula X directly from the corresponding 115,2018-dihydroxycompounds, to give the corresponding diepoxy compounds of Formula XVIH,i.e., 11/3,18;18,ZOB-diepoxy-4-pregnen-3-one 3-alkylene ketal 'and11B,18;18,20/3 diepoxy 21 hydroxy-4-pregnen-3- "one 3-alkylene ketalZI-acylate, respectively. The 21- acylates thus obtained can behydrolyzed to the 21-free alcohols in accordance with the proceduredisclosed above for hydrolyzing the compounds of Formula XVI.

The compounds of Formulae XVI, XVII and XVIII can be hydrolyzed by knownmethods for selectively hydrolyzing cyclic ketal groups, e.g., usingdilute sulfuric acid as disclosed in U.S. Patents 2,707,184 and2,758,993

to give the corresponding 3-keto compounds of Formulae VII, XIXand XIV,respectively, i.e., 18,20 3-epoxy-4-preg- I nene-3,11-dione, one,sponding 2l-hydroxy compounds and the 21-acylates llfl-hydroxy-18,20,8-epoxy-4-pregnen-3- 11,3,18;18,20,8-diepoxy-4-pregnen-3-one, the correthereof.

The compounds of Formulae VII, XIV and XIX are ""de'hydrogenated at the1,2-position by fermentative or "chemicaldehydrogenation to give thecorresponding 1- 'dehydro compounds. comprises the use of microorganismssuch as Septomyxa,

Fermentative dehydrogenation Corynebacterium, Fusarium, and the like,under fermentation conditions well known in the art, e.g., as disclosedin U.S. Patents 2,902,410 and 2,902,411. Where Septomyxa is used toeffect the dehydrogenation it is found to be advantageous to use Withthe substrate and medium a steroid promoter, such as progesterone,3-ketobisnor-4-cholen-22-al, 3-ketobisnorcholenic acid, 115,21-dihydroxy-l,4,l7(20)-pregnatrien-3-one, and the like. When the startingmaterial is a 21-oxygenated compound, the free alcohols are usuallyemployed for the fermentative dehydrogenation process. However,21-acylates of Formulae VII, XIV, and XIX can be used. In these casesthe 2l-ester group is generally saponified during the fermentationprocess giving the corresponding l-dehydro- 21-free alcohol. Chemicaldehydrogenation of the compounds of Formulae VII, XIV and XIX can becarried out with selenium dioxide according to procedures well known inthe art, e.g., as disclosed in Meystre et a1., Helv. Chim. Acta, 39 734(1956). When the starting material is a 2l-oxygenated compound theacylates are generally preferred as starting materials in the chemicaldehydrogenation reaction giving the corresponding l-dehydro-2lacylate.

Illustrative of the l-dehydro compounds thus produced are18,20/3-epoxy-1,4-pregnadiene 3,11-dione, llfl-hydroxy-l8,20,8-epoxy-1,4-pregnadien-3-one, l18,18;l8,20(idiepoxy-1,4-pregnadien-3-one, the corresponding 2l-hydroxycompounds and the 2lacylates thereof.

The 2l-acylates of Formulae VII, XIV and XIX and the correspondingl-dehydro compounds can be hydrolyzed to the corresponding 21-freealcohols by methods disclosed above for hydrolyzing the compounds ofFormula XVI.

The 2l-free alcohols of Formulae VII, XIV and XIX and the correspondingl-dehydro compounds are re-esterified to the corresponding 21-acylatesby reaction with the selected acylating agent. This reaction can beperformed under esterification conditions known in the art, e.g., by thereaction with the selected acid chloride or acid bromide or theanhydride of an organic carboxylic acid, or by reaction with theselected acid in the presence of an esterification catalyst, forexample, p-toluenesulfonyl chloride, trifluoroacetic anhydride,p-toluenesulfonic acid, trifiuoroacetic acid, sulfuric acid, and thelike, or with an ester under ester exchange reaction conditions.Compounds thus produced include those wherein the acyl radical is thatof a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms,inclusive, e.g., the acids listed in Example 3.

Moreover, the 20u-hydroxy compounds otherwise corresponding to the20,8-hydroxy starting materials hereinabove described can be substitutedas the starting materials of this invention. There are thus produced thecorresponding l8,20u-epoxy and 1lB,l8;l8,20a-diepoxy compounds whichotherwise correspond to the 18,20B-epoxy and 11,8,l8;18,20B-diepoxycompounds described in this application. These 18,20a-epoxy and11/3,l8;18,20a-diepoxy compounds have the same physiological activitiesas given hereinabove for the corresponding ZOfi-epimers and areespecially useful as antihypertensive agents.

The following preparations and examples are illustrative of the productsand process of this invention.

Preparation 1 .-3oc,20,8-dihydr0xy-5;3-pregnan- 1 l-one 3-acetate (I) Toa mixture of 45.0 g. of 3a-hydroxy-5 8-pregnane- 11,20-dione 3-acetate,600 ml. of tetrahydrofuran and 3 liters of isopropyl alcohol was added6.0 g. of sodium borohydride and 60 ml. of water. The reaction mixturewas stirred at room temperature (about 25 C.) until the reaction wascomplete (about 3.5 hours). At the end of the reaction period the excesssodium borohydride was destroyed by the cautious addition of 25 ml. ofacetic acid. The reaction mixture was then filtered and the filtrateconcentrated in vacuo to a slurry. The slurry was 9 dissolved in about500 ml. of methylene chloride and filtered. One liter of methanol wasadded to the filtrate and the solution was boiled until crystallizationoccurred. The mixture was then cooled and the crystalline product thusobtained was collected by filtration and dried to give 22.9 g. of3a,2OB-dihydroxy-5/3-pregnan-1 l-one 3-acetate (I) melting at 195-199 C.

In the same manner substituting as starting material in Preparation 13B-hydroxy-5a-pregnane-11,20-dione 3- acetate,318,21-dihydroxy-Sa-pregnane-11,20-dione 3,21- diacetate,3a,11fi-dihydroxy-5fl-pregnane-20-one B-acetate, 35,11/3-dihydroxy-5m-pregnan-ZO-ohe 3-acetate, 311,115,21- trihydroxy-Sfi-pregnan-ZO-one3,2l-diacetate, 36,115,21- trihydroxy-Sa-pregnan-ZO-One 3,2l-diacetate,4-pregnene- 3,11,20-trione S-ethylene ketal, 2l-hydroxy-4-pregnene-3,11,20-trione 3-ethylene ketal 21-acetate, llfi-hydroxy-4-pregnene-3,20-dione B-ethylene ketal or 11fi,21-dihydrxy-4-pregnene-3,ZO-dione 3-ethylene ketal Zl-acetate in place of3a-hydroxy-5B-pregnane-11,20-dione 3-acetate is productive of3B,20;8-dihydroxy-5a-pregnan-1l-one 3- acetate (1), 3a,20[3,2ltrihydroxy SB-pregnan-ll-one 3,21-diacetate (I), 38,205;1-trihydroxy-5u-pragnan-l1- one 3,21-diacetate (I),30:,11B,20B-trihydroxy-5fl-pregnane 3-acetate, 3,8,1l8,20,8-trihydroxy-a-pregnane 3- acetate, 311,115,2053l-tetrahydroxy-Sfl-pregnane 3,21- diacetate, 3B,11fi,20,8,21tetrahydroxy-5a-pregnane-3,21- diacetate,20,6-hydroxy-4-pregnene-3,ll-dione 3-ethy1ene ketal (XV),205,2l-dihydroxy-4pregnene-3,ll-dione 3- ethylene ketal Zl-acetate (XV),116,20fi-dihydroxy-4- pregnen-B-one 3-ethylene ketal and 11,8,205,21-trihydroxy-4-pregnen-3-one 3-ethylene ketal 21-acetate,respectively.

The ZOzx-hYdIOXY compounds corresponding otherwise to the ZOB-hydroxycompounds prepared and listed above can be recovered from the motherliquors by chromatography on silica gel or Florisil. After gradientelution with solvents of increasing polarity (for example, acetone inSkellysolve B) those fractions which by infrared red spectroscopy,mobility on paper chromatography or thin layer chromatography containthe desired isomer are combined and purified by crystallization, zonemelting or sublimation.

When the 3-ethylene ketals are used as the starting materials inPreparation 1, above, the excess acetic acid is neutralized with aqueoussaturated sodium bicarbonate solution before filtering and evaporatingthe solvent to prevent hydrolysis of the ketal group.

EXAMPLE A mixture of 1.00 g. of 311,2OB-dihydroxy-SB-pregnam ll-one3-acetate (I) and 60 ml. of benzene was heated at reflux. The distillatewas collected until it became clear (about 5 ml.) and then 2.00 g. ofdry lead tetraacetate was added and the mixture was allowed to refluxovernight (about 18 hours). The mixture was then cooled to about 25 C.,diluted with 100 ml. of water and treated with saturated potassiumiodide solution until no more color change occurred. The mixture wasthen treated with solid sodium thiosulfate until the mixture becameclear. The organic layer was separated, the solvent removed byevaporation in vacuo and the residue chromatographed over 100 g. ofFlorisil synthetic magnesium silicate. Elution with 3% acetone inSkellysolve B hexanes gave 0.354 g. of crude 3a-hydroxy-18,20B-epoxy-SB-pregnane-ll-one 3-acetate whichon recrystallization fromSkellysolve B hexanes gave 0.13 g. of3ahydroxy-l8,20fi-epoxy-5fl-pregnan-1l-one 3-acetate (II) melting at166-168C.

Analysis.-Calcd. for C H O C, 73.76; H, 9.15. Found: C, 73.66; H, 9.15.

In the same manner substituting 3a,20a-dihyd roxy-5;3- pregnan-ll-one3-acetate (I) as the starting steroid is productive of3a-hydroxy-18,20a-epoxy-5B-pregnan-llone-3-acetate (II).

In the same manner substituting as the starting steroid in Example 1,other compounds represented by Formula I, e.g.,35,20,8-dihydroxy-5u-pregnan-ll-one 3 acetate,3a,20fi,21-trihydroxy-55-pregnan-ll-one 3,2l-diacetate or 35,205,21trihydroxy Sa-pregnan-ll-one 3,2l-diacetate and the correspondingZOa-epimers thereof, there are thus produced as products of Example 1the corresponding 18,20 8-epoxides represented by Formula II, e.g.,3fi-hydroxy-l8,20/8-epoxy-5a-pregnan-ll-one 3-acetate, 30,21-dihydroxy-l8,20fl-epoxy-5,8-pregnan-1l-one 3,2l-diacetate and 35,21dihydroxy 18,20 3 epoxy-5a-pregnanl1-one 3,2l-diacetate, respectively,and the corresponding 20a epimers thereof, as light colored crystallinesolids.

EXAMPLE 2.3a-HYDROXY18,20fi-EPOXY-5B- PREGNAN-ll-ONE (III) A mixture of26.6 g. of 3a,2OB-dihydroxy-Sfl-pregnanll-one 3-acetate (I) and 1 literof benzene was distilled until 100 ml. of benzene was removed. Leadtetraacetate (50 g.) was then added and the mixture was heated overnightat reflux. The reaction mixture was then cooled and 500 m1. of water and10 g. of sodium iodide was added. Sodium thiosulfate g.) was added andthe mixture was shaken until it became colorless. The organic layer wasseparated and the solvent removed in vacuo. The residue, containing3a-hydroxy-l8,20B-epoxy-5fi-pregnan-ll-one 3-acetate (II), was dissolvedin 500 ml. of methanol and 20 g. of potassium hydroxide was added andthe mixture was refluxed under nitrogen for 2 hours. The mixture wascooled and neutralized with dilute aqueous hydrochloric acid. Thesolvent was then removed in vacuo and the residue thus obtained waspartitioned with methylene chloride and water. The organic layer wasseparated and the solvent removed. The crude3ahydroxy-l8,20fi-epoxy,5fi-pregnan-l1 one thus obtained was dissolvedin methylene chloride and chromatographed over synthetic magnesiumsilicate. Elution with 12% acetone in Skellysolve B hexanes gave 9.36 g.of 3u-hydroxy-l8,20B-epoxy-55-pregnan-l l-one which on ways tallizationfrom ether gave 5.25 g. of 3a-hydroxy-18,2OB- epoxy-SB-pregnan-ll-one(III) melting at 151-153C. The mother liquors were concentrated andcrystallized to give 1.46 g. of a second crop of3u-hydroxy-18,20B-epoxy- SB-pregnan-ll-one (III) melting at 148l5 1 C.

In the same manner substituting 3u-hydroxy-18,20aepoxy-SB-pregnan-ll-one3-acetate (I) as the starting steroid, is productive of3a-hydroxy-l8,20a-epoxy-S 8-pregnan-ll-one (III) In the same mannersubstituting as the starting steroid in Example 2 other compoundsrepresented by Formula I, prepared and listed in the second paragraph ofExample 1, there are thus produced the other corresponding free hydroxycompounds represented by Formula III, i.e., 3,8- hydroxy 18,2013 epoxySa-pregnan-ll-one, 3a,2l-dihydroxy-l8,20/3-epoxy-5B-pregnan-1l-one and313,21-dihydroxy-l8,20fl-epoxy-5u-pregnan-11one, respectively, and thecorresponding 20a-epimers thereof, e.g.,3a,2l-dihydr-oxy-18,20u-epoxy-5fi-pregnan-1l-one, as light coloredcrystalline solids.

EXAMPLE 3.3a-HYDROXY I8,20fl-EPOXY-5B-PREGNAN- lit-ONE 3-ACETATE (II) Asolution of 1.0 g. of 3a-hydroxy-18,20fl-epoxy-5fipregnan-l l-one (III)in dry pyridine is treated with an excess of acetic anhydride andallowed to stand at room temperature until the reaction is complete(about 24 hours). The mixture is then poured into about 250 ml. of waterand stirred at room temperature for about 2 hours. The crystallineproduct thus obtained is recovered by filtration, washed with water anddried to give 3ahydroxy-l8,20fl-epoxy-5B-pregnan-1l-one 3-acetate (II),a light colored crystalline solid identical to the product obtained inExample 1.

In the same manner substituting3a-hydroxy-18,20aepoxy-S/S-pregnan-ll-one (III) as the starting steroidis 1 l productive of 3a-hydroxy-18,20a-epoxy5,8-pregnan-11- oneS-acetate (II).

In the same manner substituting as starting material other free3-hydroxy compounds or other free 3,2l-dihydroxy compounds representedby Formula H, prepared and listed in the second paragraph of Example 2,above, in the procedure of Example 3 is productive of the correspondingacetate or diacetate, i.e., 3}8-hydroxy-l8,20[iepoxy 5a pregnan 11 one3-acetate, 3u,2l-dihydroxy- 18,20,9-epoxy-5B-pregnan-1l-one3,21-diacetate and 3,3,21- dihydroxy-l8,20fl-epoxy-5a-pregnan-l l-one 3,21-diacetate, respectively, and the corresponding 20a-epimers thereof.

The 3-free hydroxy and 3,21-free dihydroxy compounds represented byFormula III, i.e., 3a-hydroxy-l8,20B-epoxy- 5 fi-pregnan-l l-one, 3,B-hydroxyl 8,20B-epoxy-5a-pregnanll-one,3oz,21-dihydroxy-18,20,8-epoxy-5fl-pregnan-1l-one and 35,21 dihydroxy18,2018 epoxy-5a-pregnan-l1-one, and the corresponding 20a-epimersthereof, are converted to other 3-esters and 3,21-diesters by reactionwith the appropriate acid anhydride, acid chloride or bromide, ester byester exchange, acid in the presence of an esterification catalyst,etc., to produce the corresponding 3-acylates and 3,21-diacylates whichinclude those wherein the acyl radical of the acylate group is the acylradical of, for example, an aliphatic acid, e.g., acetic, propionic,butyric, valeric,

-hexanoic, lauric, trimethylacetic, isobutyric, isovaleric,

tertiary butylacetic, a cycloaliphatic acid, e.g.,B-cyclopentylpropionic, cyclohexanecarboxylic, cyclohexylacetic, analkaryl acid, e.g., benzoic, phenylacetic, B-phenylpropionic, m-, andp-toluic, a saturated dibasic acid (which can be converted into watersoluble, e.g., sodium salts), e.g., succinic, adipic, a monobasicunsaturated acid, e.g., acrylic, crotonic, undecylenic, propiolic,2-butynoic, undecolic, cinnamic, dibasic unsaturated acids (which can beconverted into water soluble, e.g., sodium, salts) e.g., maleic andcitraconic, other organic substituted acids, e.g., lactic, mandelic,salicylic, trifluoroacetic, chloroacetic, 11- and fl-bromopropionic,iodobenzoic, thioglycollic, a-arninopropionic, benzensulfonic,toluenesulfonic, 2-furoic and the like, to give the corresponding3a-hydroxy-l8,20,8-epoxy-5/3-pregnan-1l-one 3-acylate,3,8-hydroxy-18,20B-epoxy-5a-pregnan-l-one 3-acylate, 3a,2ldihydroxy18,205-epoxy-5B-pregnandl-one 3,21-diacylate and 35,21 dihydroxy18,20fi-epoxy-5a-pregnan-ll-one 3,21-diacylate, respectively, and thecorresponding 20aepimers thereof.

EXAMPLE 4.18,20fi-EPOXY-5B-PREGNANE- 3,11-DIONE (IV) To a solution of2.7 g. of 3a-hydroxy-l8,2018-epoxy-5fipregnan-ll-one (III) in 50 ml. ofacetic acid was added 2.7 g. of sodium dichromate and the mixture wasstirred at room temperature (about 25C.) for one hour. The mixture wasthen poured into 300 ml. of water with stirring. The product wascollected on a filter and washed well with Water. The product thusobtained was recrystallized from Skellysolve B hexanes to give 1.9 g. of18,ZOfl-epoxy-SB-pregnane-B,1l-dione (IV), a light colored crystallinesolid melting at 175177 C., [ab-56 (chloroform).

Analysis--Calcd. for C H O C, 76.32; H, 9.15.

'Found: C, 76.20; H, 9.24.

In the same manner substituting 3/3-hydroxy-l8,20 3-epoxy-Sa-pregnan-ll-one (III) for3a-hydroxy-18,20fiepoxy-S/i-pregnan-ll-one in Example 4, is productiveof 18,ZOB-epoxy-Sa-pregnane-3,1l-dione (IV), a light colored crystallinesolid.

EXAMPLE 5.-18,20fl-EPOXY-21-HYDROXY=5- PREGNANE-3,l1-DIONE (IV) To amixture of 1 g. of 3oz,2l-dihydroxy-18,20fi-epoxy- SIS-pregnan-ll-one(H1) in 40 ml. of toluene is added 20 ml. of cyclohexanone and asuspension of 1.0 g. of aluminum isopropoxide in 20 ml. of toluene andthe mixture is heated under refiux until the reaction is complete. Mostof the volatile material is then removed by steam distillation. Theresidue thus obtained is extracted with ethyl acetate and the combinedextracts (IV), a light colored crystalline solid.

In the same manner substituting 35,21-dihydroxy-18,20fi-epoxy-5a-pregnan-ll-one (III) for3a,2l-dil1ydroxy-18,20/3-epoxy-518-pregnan-ll-one as the startingmaterial in Example 5, is productive of 18,20 8-epoxy-21-hydroxy-5u-pregnane-3Jl-dione (IV), a light colored crystalline solid.

A mixture of 2.0 g. of 18,20fiepoxy-5/8-pregnane-3,1ldione (IV), 0.08 g.of p-toluenesulfonic acid monohydrate, 10 ml. of ethylene glycol and 100ml. of dry benzene is heated under reflux with concomitant removal ofthe water of reaction for a period of about 3.5 hours. The mixture isthen cooled, washed to neutrality with aqueous sodium bicarbonate, driedand then evaporated to dryness to leave a residue containing18,20/3-epoxy- 5fi-pregnan-3-one 3-ethylene ketal, a crystalline solid.

A mixture of this residue, 200 ml. of absolute ether and 2.0 g. oflithium aluminum hydride is prepared and allowed to stir for about 72hours. The excess hydride 'is then decomposed by the addition of ethylacetate and water. The mixture is filtered and the solvent removed fromthe filtrate to give 1lfi-hydroxy-18,20fl-epoxy-5B- pregnan-3-one3-ethylene ketal, as a light colored crystalline solid.

To a solution of the 1lp-hydroxy-l8,20fl-epoxy-5fipregnan-3 one3-ethylene ketal, thus obtained, in acetone containing 10% by volume ofwater is added 2.0 ml. of 25% sulfuric acid; the solution is allowed tostand at room temperature until hydrolysis is complete. At the end ofthe reaction excess sodium bicarbonate solution is added and the acetoneis removed in vacuo at room temperature until crystallization commences.An additional 50 ml. ofwater is then added and the crystallization isallowed to proceed at 0C. The solid material thusobtained is collectedby filtration, washed with water and dried in vacuo to give1lfi-hydroxy-18,20/8-ep0xy-5B- pregnan-3-one (VI), a light coloredcrystalline solid. The product can be further purified byrecrystallization from acetone: Skellysolve B hexanes.

In the same manner substituting as the starting material in Example 6other compounds represented by Formula IV, i.e.,18,20fi-epoxy-5u-pregnane-3,1l-dione, 18,20/3- epoxy 21 hydroxy 5 Bpregnane-3,11-dione or 18,205- epoxy-Zl-hydroxy-Sa-pregnane-El,1l-dione,there is thus produced the corresponding llfi-hydroxy compound i.e.,1lp-hydroxy-l8,20 8-epoxy-5a-pregnane-3-one, 115,21-dihydroxy-l8,20,8-epoxy-5/8-pregnan-3-one and11,8,21-dihydroxy-18,20,8-epoxy-5a-pregnan-3-one, respectively.

A solution of 3.0 g. of 18,20/8-epoxy-2l-hydroxy-Sfipregnane-3,11-dione(IV) in 20 ml. of dry pyridine is treated with 20 ml. of aceticanhydride and allowed to stand at room temperature until the reaction iscomplete (about 24 hours). The mixture is then poured into about 250 ml.of water and stirred at room temperature for about 2 hours. Thecrystalline product thus obtained is recovered by filtration, washedwith water and dried to give18,20,3-epoxy-2l-hydroxy-Sfi-pregnane-3,ll-dione 21-acetate which oncrystallization from acetone: Skellysolve B hexanes gives18,20,8-epoxy-2l-hydroxy-SB-pregmane-3,11-dione 2l-acetate, a lightcolored crystalline solid.

In the same manner substituting as the starting material in Example 7the other 21-hydroxy compounds repre- 13 sented by Formulae IV and VI,i.e., 18,20fl-epoxy-21- hydroxy-a-pregnane-3,1l-dione, 18,2OB-epoxy-1113,2l-dihydroxy-5fi-pregnan-3-one or18,20p-epoxy-115,21-dihydroxy-5a-pregnan-3-one, there are thus producedthe corresponding 21-acetates represented by Formulae V and VI.

The 21-free hydroxy compounds of Formulae IV and VI, named above, areconverted to other 21-esters by esterification of the 21-hydroxy group,e.g., by reaction with the appropriate acid anhydride, acid chloride orbromide, ester by ester exchange, acid in the presence of anesterification catalyst, etc., to produce the corresponding 21-acylateof the selected starting material represented by Formulae V and VI whichinclude those wherein the acyl radical of the 21-acylate group is theacyl radical of an acid listed in Example 3.

EXAMPLE 8.-18,20fl-EPOXY-4-PREGNENE- 3,11-DIONE (VII) A mixture of 1.05g. of 18,20fl-epoxy-5B-pregnane-3,11- dione (IV), and 40 ml. oft-butanol is stirred at room temperature with 0.5 ml. of concentratedhydrochloric acid, 1.5 ml. of water and 0.5 ml. of t-butyl hypochloritefor a period of about 2.5 hours. The reaction mixture is then dilutedwith water and extracted with methylene chloride. The extracts arecombined, washed with sodium bicarbonate solution, water, and dried oversodium sulfate. The solution is evaporated in vacuo giving 45-chloro-l8,ZOB-epoxy-SB-pregnane-B,1l-dione. The crude 4-chloro compoundis then dissolved in dimethylformamide and heated at 50-60 C. in anitrogen atmosphere with 1.38 g. of semicarbazide hydrochloride, 1.03 g.of sodium acetate and 7 m1. of water. After a period of about 2 hours,3.45 ml. of pyruvic acid and 3.45 ml. of water is added and the solutionis maintained at the same temperature for an additional period of about2.5 hours. The reaction mixture is then cooled and benzene and sodiumbicarbonate solution are added. The organic layer is separated, washedwith water and dried over sodium sulfate. The solvent is removed byevaporation in vacuo giving a residue which is dissolved in methylenechloride and chromatographed on a column of synthetic magnesiumsilicate. The column is eluted With increasing proportions of acetone inSkellysolve B hexanes. The crystalline material thus obtained iscombined and crystallized from acetone-Skellysolve B hexanes to give18,205- epoxy-4-pregnene-3,1l-dione (VII), a light colored crystallinesolid.

In the same manner substituting as the starting steroid in Example 8, an18,20B-epoxy-2l-hydroxy-SB-pregnane- 3,11-dione 21-acylate (V) preparedin Example 6, above, e.g., l8,20fl-epoxy-2l-hydroxy-5B pregnane 3,11dione Zl-acetate, there is thus produced the corresponding18,20,8-epoxy-21-hydroxy-4-pregnene-3,1l-dione 21 acylate (VII), e.g.,18,20B-epoxy-21-hydroxy-4-pregnene-3, ll-dione 21-acetate. Thecorresponding 4,8-chloro-18, B-epoxy-2l-hydroxy-5B-pregnan-3,1l-dione 21acylate is obtained as an intermediate in the reaction.

EXAMPLE 9.18,20,8-EPOXY-2l-HYDROXY- I- PREGNENE-3,11-DIONE (VII) To asolution of 3.25 g. of 18,20/3-epoxy-21-hydroxy-4- pregnane-3,11-dione21-acetate (VII) in methanol, previously purged of air-oxygen by passingnitrogen through it for ten minutes, is added a solution of 1.63 g. ofpotassium bicarbonate in ml. of water, similarly purged of oxygen. Themixture is allowed to stand at room temperature until hydrolysis iscomplete. The reaction mixture is then neutralized with acetic acid inwater and concentrated to approximately one-third volume at reducedpressure on a warm water-bath. Water is then added and the mixture ischilled. The crystalline product thus obtained is collected on a filter,washed with water and dried to give 18,20B-epoxy-21-hydroxy-4-pregnene-3,11-dione (VII), a light colored crystalline solid.

In the same manner substituting other 21-acylates of18,20,6-epoxy-21-hydroxy-4-pregnene-3,1l-dione (VII) as startingmaterial in place of the 21-acetate is likewise I4 productive of18,20,8-epoxy-21-hydroxy-4-pregnene-3,1ldione (VII).

The 18,20l3-epoxy-21-hydroxy-4-pregnene 3,11 dione (VII) can bere-esterified at the 21-position according to the procedure of Example7, above, to give the corresponding18,20fi-epoxy-21-hydroxy-4-pregnene-3, l l-dione 2l-acylate wherein theacyl radical is that of an acid listed in Example 3, above.

EXAMPLE 10.10,20B EPOXY-5fl-PREGNANE-3a,l15-

DIOL-3-ACETATE (IX) A mixture of 9.7 g. of 3u-hydroxy-18,20B-epoxy-5B-pregnan-ll-one 3-acetate (II) (chromatograph fractions), 400 ml. ofabsolute ether and 4.0 g. of lithium aluminum hydride were combined andallowed to stir about 72 hours. The excess hydride Was decomposed by theaddition of 10 ml. of ethyl acetate and then 5 ml. of water. The mixturewas filtered and the solvent removed from the filtrate to give 1.45 g.of 18,20fl-epoxy-5fl-pregnane- 30:,115-di0l (VIII), as a whitecrystalline solid. The filtered solids were resuspended in and filteredsuccessively from hot ethyl acetate, tetrahydrofuran, and finallypyridine. The solvents were then removed under reduced pressure to yieldan additional 9.2 g. of 18,20,3-epoxy-5flpregnane-3a,11B-diol (VIII) asa light colored crystalline solid. The18,20fi-epoxy-Sfl-pregnane-Sa,1lfi-diol yields were combined andsuspended in 30 ml. of pyridine and 15 ml. of acetic anhydride andallowed to stir overnight. The mixture was then filtered to remove theinorganic material (1.24 g.). The filtrate was poured into dilutehydrochloric acid and extracted with methylene chloride. The extract waswashed with saturated sodium bicarbonate 'solution and the solventremoved by evaporation at reduced pressure. The residue thus obtainedwas recrystallized from absolute ether to yield 3.42 g. of 18,20B-ep0xy-5,8 pregnane 3a,11[3 diol 3 acetate (IX) melting at 169-172 C.

Analysis.Calcd. for C I-I O C, 73.36; H, 9.64. Found: C, 73.36; H, 9.90.

In the same manner susbtituting 3a-hydroxy-18,20aepoxy-SB-pregnan-ll-one3-acetate (II) as the starting steroid is productive of18,20a-epoxy-5fi-pregnane 3a, 11 8-diol3-acetate (IX).

In the same manner substituting as the starting steroid in Example 10other compounds represented by Formula II for example, the 21-acetatesprepared and listed in the second paragraph of Example 2, i.e.,3fi-hydroxy-l8,20fiepoxy-Sa-pregnan-l l-one 3-acetate,3a,2l-dihydro-xy-l18,

20fi-epoxy-5/3-pregnan-1l-one 3,21-diacetate and3,8,21-dihydroxy-l8,20B-epoxy-5u-pregnan-11-one 3,21 diacetate and thecorresponding ZOa-epimers thereof, e.g., 3a,2l-dihydroxy-l8,20a-epoxy-5B-pregnan-1l-one 3,21 diacetate, there is thusproduced the corresponding llfl-hydroxy compound represented by FormulaIX, i.e., 18,2OB-epoxy- 5 a-pre gnane-3 5,1 1fl-diol-3-acetate,18,20fi-epoxy-5/3-pregnane-3a,11,8,21-triol 3,21-diacetate and18,20B-6POXY-5ocpregnane-313,113,21-triol 3,21-diacetate, respectively,and the corresponding 20a-epimers thereof, e.g., 18,200:-epoxy-5B-pregnane-3a,11,8,21-triol 3,21-diacetate, the correspondingfree hydroxy compounds of Formula VIII are likewise produced asintermediates in the reaction.

In the same manner other acylates represented by Formula II, preparedand named in Example 3, or the corresponding free hydroxy compoundsrepresented by Formula III, prepared and named in Example 2, can besubstituted as starting material in place of the acetate in theprocedure of Example 10 to produce the same corresponding 11 B-hydroxycompounds, i.e., 18,20,6-epoxy-5fl-pregmane-3 0:,11 8-di01 3-acetate,18,ZOB-epoxy-Sa-pregnane-3,8, llfi-diol 3 -acetate, 18,20/8-epoxy-5,8-pregnane-3a,1 1,8,21- triol 3,21-diacetate and18,20/3-epoxy-5a-pregnane-3 8,l1B, 21-triol 3,21-diacetate, and thecorresponding 20a-epimers thereof.

In the same manner other acid anhydrides of hydrocarbon carboxylicacids, for example those acids listed in Example 3 can be substituted inplace of acetic anhydride in the procedure of Example 10 to produce thecorresponding 3-acylates and 3,2l-diacylates (IX), i.e., 18,20B-epoxy-5;8-pregnane-3a,l1B-dio1 3-acylate, 18,20fi-epoxy-5a-pregnane-3fl,ll3-diol 3-acylate, 18,20fl-epoxy-5 8-pregnane-3a, 115,21-triol3,2l-diacylate and l8,20fi-epoxy-5a-pregnane- 35,115,21-triol3,21-diacylate and the corresponding aepimers thereof.

The 3-acetates, 3,2l-diacetates or other corresponding 3- acylates and3,21-diacylates thus prepared can be hydrolyzed in accordance with thehydrolysis procedure of Example 2 above, e.g., with sodium hydroxide inmethanol to give the corresponding free hydroxy compounds, i.e., 18,20 3epoxy-5,8-pregnane-3a,11,8-diol, 18,20/3-epoxy-5apregnane 3,8,11,6-dio1,18,20fi-epoxy-5flpregnane-3a,1 1B, 21-triol andl8,20,8-epoxy-5a-pregnane-3,8,11,8,21-triol and the correspondingZOa-epimers thereof.

EXAMPLE '11.11B,1S;18,20B-DIEPOXY5B-PREGNAN 3a-OL S-ACETATE (X) Amixture of 3.5 g. of 18,20,8-epoxy-5fl-pregnane-3a, llfl-diol 3-acetate(IX) and 350 ml. of benzene was distilled until about 50 ml. ofdistillate was removed, 7.0 g. of lead tetraacetate was then added andthe mixture was refluxed for about 18 hours. The mixture was then cooledand 100 ml. of water and 1.0 g. of sodium iodide was added. Then 20.0 g.of sodium thiosulfate was added and the mixture shaken until the iodinecolor disappeared. The organic layer was separated and washed withsaturated aqueous sodium bicarbonate. The solvent was removed in vacuoto give 3.43 g. of a crystalline residue containing 11fl,18;18,20,8diepoxy-5 3-pregnan-3a-ol 3-acetate. The product thus obtained wasdissolved in methylene chloride and chromatographed over a column ofsynthetic magnesium silicate. The column was eluted with Skellysolve Bhexanes containing increasing proportions of acetone. The fractioneluted wit-h 3% acetone in Skellysolve B hexanes gave 1.981 g. of11,3,18;18,20fi-diepoxy-5fi-pregnan-3a-ol 3-aeetate (X), which can befurther purified by recrystallization from acetone-Skellysolve Bhexanes.

In the same manner substituting 18,20a-epoxy-5 3-pregnane-3a,1lfl-diol3-acetate (IX) as the starting steroid is productive of116,18;18,20a-diepOXy-Sfi-pregnane-3a-ol 3- acetate (X).

In the same manner substituting as the starting steroid in Example 11other acetates represented by Formula II prepared and listed in thesecond paragraph of Example 10, there is thus produced the correspondingdiepoxy compounds represented by Formula X, i.e., 11 [3,18,18,203-diepoxy-5ot-pregnane-3fi-ol 3-acetate, l1fi,18;18,20fl-diepoxy-3fi-pregnane-3a,2l-diol, 3,21-diacetate and 11,8,18;18,20B-diepoxy-5a-pregnane-3fl,2l-diol 3,21-diacetate, respectively, and thecorresponding 20 -ep-imers thereof, e.g., 1118,18;l8,20a-diepoxy-5fi-pregnane-3 11,2 l-diol 3 ,21-diacetate.

In the same manner substituting as starting material in Example 11 otheracylates in place of the acetates there are thus produced thecorresponding diepoxy compounds of Formula X, i.e.,11fi,18;18,2OB-diepoxy-Sfl-pregnane-3aol 3-acylate, 118,l8;18,20,B-diepoxy-5oz-pregnane-3fl-ol 3- acylate, 115,183 8,203-diepoxy-5fi-pregnane-3a,2l-dial 3, 21 diacylate and 113,18;18,20fi-diepoxy-5a-pregnane-3/3, 2l-diol 3,21-diacylate and thecorresponding 20a-epimers thereof, wherein the acyl radical is that ofan acid listed in the third paragraph of Example 3.

EXAMPLE 12.11fi.18;18,2OB-DIEPOXY-5fl PREGNANE- 3u-OL 3-ACETATE (X) Amixture of 1.00 g. of 3a,l1fl,20fl-trihydroxy-5fipregnane 3-acetate and60 ml. of benzene is heated at reflux. The distillate is collected untilit becomes clear (about 5 ml.) and then 4.0 g. of dry lead tet-raacetateis graphed over 100 g. of synthetic manesium silicate. Elution with 3%acetone in Skellysolve B hexanes gives crude11,8,18,18,205-diepoxy-5B-pregnane-3 u-ol 3-acetate which onrecrystallization from Skellysolve B hexanes gives 11ft, l8;l8,20,8diepoxy 5/3-pregnan-3a-ol 3-acetate (X), a light colored crystallinesolid.

In the same manner substituting 3a,l1/3,20a-trihydroxy- SB-pregnane3-acetate as the starting steroid is productive of11,B,l8;18,20ot-diepoxy-5fi-pregnan-3a-ol S-acetate (X).

In the same manner, substituting as the starting steroid in Example 12,35,115,20,8-trihydroxy-5a-pregnane 3-acetate,3a,11fi,205,2l-tetrahydroxy-Sfl-pregnane 3,21-diacetate,3,8,11;3,20/3,21-tetrahydroxy-5a-pregnane 3,2l-diacetate or thecorresponding ZOa-epimers thereof is productive of11,8,18;18,20fi-diepoxy-5a-p.regnan-3B-ol 3-acetate, 11B, 18;l8,20fldiepoxy-5/8-pregnane-3a,2l-diol 3,2l-diacetate and 11,3,18;18,203-diepoxy-5a-pregnane-3,8,21-diol 3,2l-diacetate, respectively, and thecorresponding 20a-epimers thereof, e.g., l1[3,l8;l8,20adiepoxy-5fi-pregnane3a,21- diol 3,21-diacetate.

EXAMPLE 13.11 S,18;18.20B-DIEPOXY-5fl- PREGNAN-3a-OL (XI) A solution of2.0 g. of 116,1838,20,8-diepoxy-5fl-pregnan-3a-ol 3-acetate (X) in 100ml. of methanol was treated with 0.56 g. of potassium hydroxide undernitrogen. After stirring for 16 hours, the base was neutralized by theaddition of 0.65 ml. of acetic acid. The solvent was evaporated in vacuoand the residue thus obtained was recrystallized from absolute ether togive 1.34 g. of 1118,18; l8,ZOB-diepoXy-Sfl-pregnan-Ba-ol (XI) meltingat 181- 184 C.

In the same manner substituting for the 1l3,l8;18,20adiepoxy-Sfl-pregnan-h-ol 3-acetate (X) as the startingsteriod is productive of 11B,18;18,20a-diepoxy-5 3-pregnan- 3a-ol (XI).

In the same manner substituting as the starting steroid in Example 13other acetates represented by Formula X, prepared and listed in thesecond paragraph of Example 12, there is thus produced the correspondingfree hydroxy compounds represented by Formula XI, i.e., 11fl,18;18,20fi-diepoxy-5a-pregnan-3fl-ol, 11;8,18;l8,20fi-diepoxy-5fipregnane3a,2l-diol and 113,18;18,20,13-diepoxy-5a-pregnane-3/8,21-diol,respectively, and the corresponding 20aepimers thereof, e.g.,115,18,18,20a-diepoxy-5 8-pregnane- In the same manner other acylatescan be substituted for the acetates to produce the same free hydroxycompounds.

The free hydroxy compounds thus obtained can be reesterified inaccordance with the procedure of Example 3 to produce the correspondingacyloxy compounds of Formula X wherein the acyl radical is that of anacid listed in Example 3.

EXAMPLE 14.11fi,18;18.20,6- IEPOXY-5fl- PREGNAN-3-ONE (XII) A solutionof 1.60 g. of 11;8,l8;18,20fi-diepoxy-5B- pregnan-3a-ol (XI) in about 20ml. of acetic acid was treated with 1.60 g. of sodium dichromatedihydrate. The mixture was then stirred for a period of about one hourat room temperature (about 25 C.) and then poured into ml. of water. Thecrystalline product thus obtained was collected on a filter, washed wellwith water and dried to give 1.43 g. of crude 11B,l8;l8,20,8-diepoxy-5fl-pregnan-3-one. The crude product was recrystallized from methanol togive 1lfl,18;18,20 3-diepoxy-5 3-pregnan-3-one (XII) melting at 179183C.

Analysis-Calcd. for C H O C, 76.32; H, 9.15. Found: C, 75.93; H, 9.21.

In the same manner substituting 11B,18;18,20m-diepoxy- 5 3-pregnan-3-ol(XI) as starting steroid is productive of 116,18;18,ZOa-diepoxy-S,6-pregnan-3 -one (XII).

In the same manner substituting 11B,l8;18,20}3-diepoxy-5a-pregnan-3fl-ol (XI) or the corresponding ZOa-epimer thereof as thestarting steroid in Example 14 is productive of113,18;18,20fi-diepoxy-5a-pregnan-3-one (XII) and the corresponding20a-epimer thereof, respectively, as light colored crystalline solids.

EXAMPLE 15.11 3,18 ;18,205-DIEPOXY-21-HYDROXY- To a mixture of 1.0 g. of11B,18;18,20B-diepoxy-5fipregnane-3a,21-diol (XI) and 40 ml. of tolueneis added 20 ml. of cyclohexanone and a suspension of 1.0 g. of aluminumisopropoxide in 20 ml. of toluene and the mixture is heated under refluxuntil the reaction is complete. Most of the volatile material is thenremoved by steam distillation. The residue thus obtained is extractedwith ethyl acetate and the combined extracts are washed with aqueoussodium bicarbonate solution and water and dried over sodium sulfate. Thesolvent is then removed by evaporation and the residue thus obtained ispurified by chromatography and crystallization to give 11/3,l8;18,20/3-diepoxy-Zl-hydroxy SB-pregnan-B-one (XII), a light colored crystallinesolid.

In the same manner substituting 11B,18;18,20a-diepoxy-5,8-pregnane-3u,21-diol (XI) as starting material is productive of1113,18;18,20a-diepoxy-2l-hydroxy-SB-pregnan- 3-one (XII).

In the same manner substituting11B,18;18,20fl-diepoxya-pregnane-3B,21-diol (XI), or the corresponding200cepimer thereof, as the starting material in Example 15 is productiveof 1 1,8,18;l8,20B-diepoxy-2I-hydrQXy-Sa-pregnan-3-one (XII) and thecorresponding 20a-epimer, respectively, as light colored crystallinesolids.

EXAMPLE 16.l16,1S;1S,205 DIEPOXY-21-HYDROXY-5B- PREGNEN-3-ONE 21-ACETATEXIII) AND 115,18 ;18, 205-DIEPOXY-21-HYDROXY 5a PREGNAN-3-ONE 21 ACETATE(XIII) Substituting an equivalent amount of 11fi,18;18,20,8-diepoxy-21-hydroxy-5,B-pregnan-3-one (XH), 11B,18;18,205-diepoxy-21-hydroxy-5a-pregnan-3-one (XII) or the corresponding20a-epimers thereof, e.g.,11B,18;18,20adiepoxy-21-hydroxy-5{3-pregnan-3-one (XIII) as the startingsteroid in Example 7, above, in place of 18,20,8-epoxy- 21hydroxy-5fi-pregnane-3,1l-dione is productive of 113,18;18,20fl-diepoxy-21-hydroxy-5B-pregnan-3 -one 21-acetate and11,8,18;18,20,8-diepoxy-21-hydroxy-5u-pregnan-3- one 21-acetate,respectively, and the corresponding 200cepimers thereof, e.g.,116,18;18,20a-diepoxy-21-hydroxy- 55-pregnan-3-one 21-acetate.

The 21-free hydroxy compounds of Formula XII, named above, are convertedto other 21-esters by esterification of the 21-hydroxy group, e.g., byreaction with the appropriate acid anhydride, acid chloride or bromide,ester by ester exchange, acid in the presence of an esterificationcatalyst, etc., to produce the corresponding 21-acylate of the selectedstarting material represented by Formula XIII which include thosewherein the acyl radical of the 21- acylate group is the acyl radical ofan acid listed in Example 3.

EXAMPLE 17.--11fi,18;18,20 8DIEPOXY-4- PREGNEN-3-ONE (XIV) A mixture of1.12 g. of 11B,18;18,20[3-diepoxy-5fipregnan-3-one, 40 ml. of t-butylalcohol, 0.5 ml. of t-butyl hypochlorite and dilute hydrochlorite acid(0.5 ml. of concentrated hydrochloric acid and 1.5 ml. of water) wasstirred at room temperature (about 25 C.) for a period of about 2.5hours giving a white precipitate. The precipitate thus obtained wascollected on a filter and dried to give 0.37 g. of4,8-chloro-11B,18;18-20 6-diepoxy-5fipregnan-3-one melting at 193196 C.with decomposition.

A mixture of the 4-chloro compound thus obtained, 8 ml. of redistilleddimethyl formamide, 0.45 g. of semicarbazide hydrochloride, 0.34 g. ofsodium acetate and 2 ml. of Water was heated at about 60 C. for a periodof about 2 hours. Then 1.2 ml. of pyruvic acid and 1.2 m1. of water wasadded and heating at about 60 C. was continued for an additional periodof about 2.5 hours. The reaction mixture was then poured into about 200ml. of a mixture of ice and water with stirring and then filtered togive 0.213 g. of a crystalline white solid. The product thus obtainedwas dissolved in methylene chloride and chromatographed over syntheticmagnesium silicate. Elution with 5% acetone in Skellysolve B hexanesgave 0.134 g. of 116,18;18,205-diepoxy-4-pregnen-3-one.Recrystallization from methanol gave an analytical sample of 116,18;18,205-diepoxy-4-pregnen-3-one (XIV) melting at 201- 203 C., [a] +140in chloroform.

In the same manner substituting 11,6,18;18,20a-diep0xy-5,8-pregnane-3-one as the starting steroid is productive of11fi,18;18,20a-diepoxy-4-pregnene-3-one (XIV).

In the same manner substituting as the starting steroid in Example 17,11,6,18;18,20,8-diepoxy-2l-hydroxy-SB- pregnan-3-one 21-acylate (XIII)or the corresponding ZOa-epimer thereof prepared in Example 16, above,e.g., 1 15,18;18,205-diepoxy-21-hydroxy-5p-pregnan-3-one 21- acetate or1113,18;l8,20a-diepoxy-2l-hydroxy-Sfi-pregnan- 3-one 2l-acetate, thereis thus produced the corresponding1113,18;18,20,8-diepoxy-2l-hydroxy-4-pregnen-3-one 21 acylate (XIV) andthe corresponding 20a-epimer, respectively, e.g.,11,8,18;18,20,8-diepoxy-21-hydroxy-4-pregnen- 3-one 21-acetate and1lfl,18;18,20a-diepoxy-2l-hydroxy- 4-pregnen-3-one ZI-acetate. Thecorresponding 45- chloro l1,8,18;18,20B-diepoxy-21-hydroxy-5B-pregnan-3one 21-acylate and the corresponding 20a-epimer thereof are obtained asintermediates in the reaction.

4-PREGNEN-3-0NE (XIV) Following the procedure of Example 9 butsubstituting an equivalent amount of 1 1/3,1 8;18,2013- diepoxy-21-hydroxy-4-pregner1-3-one 21-acetate (XIV) or the corresponding ZOa-epimerthereof for 18,20,6-epoxy-21-hydroxy-4-pregnene-3,1l-dione 21-acetate isproductive of 11fl,18;18,20B-diepoxy-2l hydroxy 4 pregnen 3 one (XIV)and 115,1 8;18,20u-diepoxy-21-hydroxy-4-pregnen- 3-??? (XIV),respectively, as light colored crystalline s01 s. i

In the same manner substituting other 21-acylates of 11,8,18;18,20fi-diepoxy-2l-hydroxy-4 pregnan 3 one or other 21-acylatesof the corresponding 20a-epimer thereof as the starting material inplace of the 21-acetate is likewise productive of11B,18;18,20/3-diepoxy-21-hydroxy-4- pregnen-3-one (XIV) and thecorresponding ZOa-epimer thereof, respectively.

The 1=1B,18;18,20,6-diepoxy-21-hydroxy 4 pregnene-3- one (XIV) and thecorresponding 20a-epimer thereof can be re-esterified at the 21-positionaccording to the procedure of Example 7, above, to give thecorresponding 21- acylate wherein the acyl radical is that of an acidlisted in Example 3, above.

EXAMPLE 19.18,20f3-EPOXY-4-PREGNENE-3,1l-DIONE 3-ETHYLENE KETAL (XVI) Amixture of 5.3 g. of 20,8-hydroxy-4-pregnene-3,1l-dione 3-ethylene ketal(XV) and 350 ml. of benzene was distilled until 50 ml. of benzene wasremoved; 11.5 g. of lead tetraacetate was then added and the reactionmixture was heated at reflux overnight (about 12 to 14 hours). Themixture was then cooled and ml. of water and 10 g. of sodium thiosulfatewas added with stirring. The mixture was filtered through celitediatornaceous earth and the celite was Washed with methylene chloride.The methylene chloride was separated from the water layer, washed Withaqueous sodium bicarbonate solution and evaporated to remove thesolvent. The residue thus obtained was redissolved in methylene chlorideand chromatographed on 400 g. of synthetic magnesium silicate. acetonein Skellysolve B hexanes gave 1.07 g. of 18,205-epoxy-4-pregnene-3,11-dione S-ethylene ketal (XVI), a light coloredcrystalline solid. The infrared spectrum supported the assignedstructure.

In the same manner substituting20a-hydroxy-4-pregnene-3,11-dione-3-ethylene ketal (XV) as the startingsteroid is productive of 18,20a-epoxy-4 pregnene-3,1l-dione 3-ethyleneketal (XVI).

In the same manner substituting 20,8,2l-dihydroxy-4- Elution with 5%- 19pregnene-3,11-dione 3-ethylene ketal 21-acetate (XV) or thecorresponding ZOoc-GPIIIICI thereof as the starting steroid in Example19 is productive of 18,20/8-epoxy-2lhy droxy-4-pregnene-3,20-dione3-ethylene ketal 21-acetate (XVI) and the corresponding ZOa-epimerthereof, respectively, which can be hydrolyzed in accordance with theprocedure of Example 9 to give 18,20,8-epoxy-21-hydroxy-4-pregnene-3,-20-dione 3-ethylene ketal and the corresponding ZOu-epimerthereof, respectively. The 21-hydroxy compounds thus produced can bere-esterified in accordance with the procedure of Example 7, above, togive the corresponding 18,20fl-epoxy-21-hydroxy-4-pregnene-3,20-dione3-ethylene ketal 21-acylate and the corresponding 20a-epimer thereof,respectively, wherein the acyl radical is that of an acid named inExample 3.

EXAMPLE 20.18,20fl-EPOXY-4-PREGNENE 3,11-DIONE (VII) A mixture of 2.20g. of crude 18,20fi-epoxy-4-prcgnene- 3,11-dione ethylene ketal (XVI),50 ml. of acetone, 10 ml. of methylene chloride, 10 ml. of methanol and10 ml. of water containing 10 drops of sulfuric acid was stirred for 16hours at room temperature (about 25 C.). The reaction mixture was thenneutralized with saturated aqueous sodium bicarbonate solution, pouredinto water and extracted with methylene chloride. The solvent wasremoved by evaporation to give 2.17 g. of residue which was redissolvedin methylene chloride and chromatographed over 200 g. of syntheticmagnesium silicate. Elution with 10% acetone in Skellysolve B hexanegave 1.45 g. of 18,20B-epoxy-4-pregnene-3,1l-dione. Tworecrystallizations, one from acetone-Skellysolve B hexanes and one fromaqueous methanol, yielded 0.74 g. of 18,20,8-epoxy-4-pregnene-3,11-dione (VII) melting at 163 to 173 C.

Analysis.Calcd. for C H O C, 76.79; H, 8.59. Found: C, 76.92; H, 8.62.

In the same manner substituting18,-20B-epoxy-2l-hydroxy-4-pregnene-3,1l-dione 3-ethylene ketal or a21-acylate thereof (XVI) as the starting steroid in Example 20 isproductive of l8,20,8-epoxy-21hydroxy-4-pregnene-3,11- dione (VII) andthe corresponding 18,-20B-epoxy-2l-hydroxy-4-pregnene-3,1l-dione21-acylate, respectively. EXAMPLE 21.11B-HYDROXY-18,2OB-EPOXY-4-PREGNEN-3ONE 3-ETHYLENE KETAL (XVII) AND 11fi,1S;18,20B-

DIEPOXY 4 PREGNEN-Ei-ONE 3 ETHYLENE KETAL (XVIII) A mixture of 400 mg.of 18,20B-epoxy-4-pregnene-3,11- dione 3-ethylene ketal and 30 ml. ofabsolute ether was reacted with 200 mg. of lithium aluminum hydride andallowed to stir at room temperature (about 25 C.) for a period of about2 hours. The excess hydride was decomposed by the cautious addition ofethyl acetate and then water. The mixture was then filtered throughcelite diatomaceous earth to remove the solid inorganic salts. Thefilter cake was washed with ethyl acetate and actone and the washes werecombined with the filtrate. The filtrate was then evaporated to removethe solvent giving 0.57 g. of a white solid residue containing inorganicmaterial. The residue was leached with boiling benzene and the benzenewas evaporated to give 0.40 g. of 1l/3-hydroxy-18,20fi-epoxy-4-pregnene-3-one 3-ethylene ketal, a white crystalline solid.The infrared spectrum of this material indicated that it had beencompletely reduced.

The 1lfi-hydroxy-l8,20fl-epoxy-4-pregnen-3-one 3-ethylene ketal thusobtained was dissolved in about 25 ml. of benzene, 2.0 g. of leadtetracetate was added and the mixture was allowed to reflux for a periodof about 16 hours. At the end of the reflux period 10 ml. of water and3.0 g. of sodium thiosulfate were added with stirring. The organic layerwas separated, then washed with water and aqueous sodium bicarbonate.The solvent was removed by evaporation and the residue thus obtained wasdissolved in methylene chloride and chromatographed over 30 g. ofsynthetic magnesium silicate. Elution with 4% acetone in Skellysolve Bhexanes gave 0.050 g. of 1lfi,l8;18,20',6-d1- 20 epoxy-4-pregnene-3-one3-ethylene ketal. Recrystallization from aqueous methanol gave ananalytical sample of l15,18;18,20fi-diepoxy-4-pregnene-3-one 3-ethylenek tal (XVIII) melting at 232 to 236 C.,

' gl'i 1670, 1165-10020111."

Analysis.Calcd. for C H O C, 74.16; H, 8.66. Found: C, 74.29; H, 8.78.

Further elution with 4% acetone in Skellysolve B hexanes eluted 0.211 g.of the starting material for the lead tetraacetate reaction which wasrecrystallized from aqueous methanol to give1lfi-hydroxy-l8,20fl-epoxy-4- pregnene-3-one 3-ethylene ketal (XVII)melting at 232 to 236 C.;

Analysis.Calcd. for C H O C, 73.76; H, 8.15. Found: C, 73.91; H, 8.84.

In the same manner substituting l8,20a-epoxy-4-pregnene-3,11-dione3-ethylene ketal as the starting steroid is productive ofllfl-hydroxy-l8,20a-epoxy-4-pregnen-3- one 3-ethylene ketal (XVII) and11fi,18;18,20a-diepoxy- 4-pregnen-3-one 3-ethylene ketal (XVII).

In the same manner substituting18,20/3-epoxy-2l-hydroxy-4-pregnene-3,ll-dione 3-ethylene ketal (XVII)or the corresponding ZOa-epimer thereof as the starting steroid inExample 21, there is thus produced as a product of the lithium aluminumhydride reaction 18,20,6- epoxy-l15,21-dihydroxy-4-pregnen-3-one3-ethylene ketal (XVII) and the corresponding ZOu-epimer thereof,respectively, which are then acylated at the 21-position with aceticanhydride to give 18,20,8-epoxy-l1fi,21-dihydroxy- 4-pregnen-3-one3-ethylene ketal 21-acetate (XVII) and the 20u-epimer thereof,respectively, which on treatment with lead tetraacetate givellfl,18,18,20B-diepoxy-2l-hydroxy-4-pregnen-3-one 3-ethylene ketal2l-acetate and 1113,18;18,20oc-diepoxy-2l-hydroxy-4-pregnen-3-one3-ethylene ketal 21-acetate (XVIII), respectively.

EXAMPLE 22.--11B,18;18,20 3-DIEPOXY-4-PREGNEN- 3-ONE 3-ETHYLENE KETAL(XVIII) A mixture of 1.00 g. of 115,20,8-dihydroxy-4-pregnen- 3-oneS-ethylene ketal and 60 ml. of benzene is heated at reflux. Thedistillate is collected until it becomes clear (about 5 ml.) and then4.0 g. of dry lead tetraacetate is added and the mixture is allowed toreflux about 18 hours. The mixture is then cooled to about 25 C.,diluted with about ml. of water and treated with saturated potassiumiodide solution until no more color change occurs. The mixture is thentreated with solid sodium thiosulfate until the mixture becomes clear.The organic layer is separated, the solvent removed in vacuo and theresidue chromatographed over 100 g. of synthetic magnesium silicate.Elution with acetone in Skellysolve B hexanes gives crude115,18;18,20B-diepoxy-4-pregnen-3-one 3-ethylene ketal which onrecrystallization from acetone-Skellysolve B hexanes gives115,18;18,20,8-diepoxy-4-pregnen- 3-one 3-ethylene ketal which onrecrystallization from acetone-Skellysolve B hexanes givesll,8,l8;l8,20fl-diepoxy-4-pregnen-3-one 3-ethylene ketal (XVIII), alight colored crystalline solid.

In the same manner substituting llfi,20a-dihydroxy-4- pregnen-3-one3-ethylene ketal as the starting steroid is productive of1lfi,l8;18,20a-diepoxy-4-pregnen-3-one 3- ethylene ketal (XVIII).

In the same manner substituting llB,20 B,21-trihydroxy- 4-pregnen-3-one3-ethylene ketal 21-acetate (XVIII), or the corresponding ZOa-epimerthereof, as the starting steroid in Example 22 is productive of11,13,18;18,20[3-diepoxy-2l-hydroxy-4-pregnen-3-one S-ethylene ketal 21-acetate (XVIII), and the corresponding 20a-epimer thereof, respectively,which can be hydrolyzed according to the procedure of Example 9, above,to give l16,18;l8,20fidiepoxy 21 hydroxy-4-pregnen-3-one 3-ethyleneketal (XVIII), and l15,18;l8,20rx-diepoxy-2l-hydroxy-4-pregnen-3-one3-ethylene ketal (XVIII), respectively. The

21 free 21-hydroxy compounds thus obtained can be re-esterified inaccordance with the procedure of Example 7, above, to give thecorresponding 11/3,18;18,20fl-diepoxy- 2l-hydroxy-4-pregnen-3-one3-ethylene ketal 2l-acylate, and the corresponding ZOa-epimer thereof,wherein the acyl radical is that of an acid listed in the thirdparagraph of Example 3.

EXAMPLE 23.11fi,18;18,20t3-DIEPOXY-4- PREGNEN-3-ONE (XIV) A mixture of0.110 g. of 115,1838,20B-diepoxy-4-pregnen-3-one 3-ethylene ketal, 15ml. of acetone and 5 m1. of water containing 5 drops of concentratedsulfuric acid was allowed to stand overnight at room temperature (about25 C.). The mixture was then poured into water, neutralized withsaturated aqueous sodium bicarbonate solution and extracted withmethylene chloride. The solvent was then removed in vacuo and theresidue thus obtained was dissolved in methylene chloride andchromatographed over 20 g. of Florisil synthetic magnesium silicate.Elution with 8% acetone in Skellysolve B hexanes gave 0.061 g. of11,8,18;18,20/i-diepoxy-4-pregnen-3-one (XIV); the infrared spectrum ofthis compound was identical to that obtained in Example 17.

In the same manner substituting ll5,18;l8,20u-diepoxy- 4-pregnen-3-one3-ethylene ketal as starting material is productive of l1fi,18;18,20ocdiepoxy-4-pregnen-3-0ne (XIV).

EXAMPLE 24.111S HYDROXY 18,205-DIEPOXY- 4PREGNEN-30NE (XIX) Followingthe procedure of Example 23 but substituting an equivalent amount ofl1,8-hydrxy-l8,20t3-epoxy- 4-pregnen-3-one 3-ethylene ketal (XVII) asstarting material in place of 11,8,18;18,20B-diepoxy-4-pregnen-3-one isproductive of llB-hydroxy-l8,20fi-epoxy-4-pregnen-3-one, a light coloredcrystalline solid.

In the same manner substituting 115,2l-dihydroxy-l8,20,8-epoxy-4-pregnen-3-one 3-ethylene ketal (XVII), llfl,18;18,20B-diepoxy-2l-hydroxy-4-pregnen-3-one 3-ethylene ketal (XVIII) or11,8,l8;18,20a-diepoxy-2l-hydroxy-4- pregnen-3-one 3-ethylene ketal(XVIII), as the starting steroid in Example 22 is productive of11,3,2l-dihydroxy- 18,2OB-epoxy-4-pregnen-3-one (XIX),11B,18;18,20B-diepoxy-21-hydroxy-4-pregnen-3-one (XIV), and 11 5,1838,20a-diepoxy-2l-hydroxy-4-pregnen-3-one (XIV), respectively. These2l-hydroxy compounds thus produced can be esterified at 21-position inaccordance with the procedure of Example 7, above, to produce thecorresponding 1 l {3,2l-dihydroxy-18,20B-epoxy-4-pregnen-3-one 3-acylate(XIX), 11,8,l8;18,20,8 diepoxy-21-hydroxy-4-pregnen-3- one 21-acylate(XIV) and the corresponding ZOOc-GPIIHGIS thereof, respectively, whereinthe acyl radical is that of an acid listed in the third paragraph ofExample 3.

Alternatively, the 21-acylates represented by Formulae XVII and XVIIIcan be substituted as the starting steroid in Example 23 to produce thecorresponding deketalized ZI-acylates of Formulae XIX and XIV, named inthe preceding paragraph.

EXAMPLE 25.18,20flEPOXYJA-PREGNADIENE- 3,11-DIONE Five 100 ml. portionsof a medium, in 250 ml. Erlenmeyer flasks, containing 1% glucose, 2%corn steep liquor (60% solids) and tap water are adjsted to a pH of 4.9.This medium is sterilized for 45 minutes at 15 p.s.i. and inoculatedwith a one to two day vegetative growth of Septomyxa afiinis ATCC 6737.The Erlenmeyer flasks are shaken at room temperature (about 26 to 28 C.)for a period of about three days. At the end of this period this 500 ml.volume is used as an inoculum for 10 liters of the same glucose-cornsteep liquor medium which in addition contains m., of an antifoamcompound (a mixture of lard oil and octadecanol). The fermentor isplaced into the water-bath, adjusted to 28 C. and the contents stirredthoroughly (300 r.p.m.) and aerated (0.1 liter of air per minute toliters of beer). After 20 hours of incubation, when a good growth hasbeen developed, 1.0 g. of 18,20/3-epoxy-4-pregnene-3,1l-dione (VII) plus50 mg. of 3-ketobisnor-4-cholen-22-al dissolved in dimethylformamide isadded and the incubators carried out at the same temperature (28 C.) andaeration until the reaction is complete (final pH 8.3). The mycelium isfiltered olf and extracted with three 200 ml. portions of acetone. Thebeer is extracted with three 1 liter portions of methylene chloride andthereupon the acetone extracts and the extracts of beer are combined,dried over anhydrous sodium sulfate and evaporated and the resultingresidue chromatographed over an anhydrous magnesium silicate column,which on elution with Skellysolve [3 hexanes containing increasingproportions of acetone from 1 to 50% and crystallization gives 18,205-epoxy-1,4-pregnadiene-3,1l-dione, a light colored crystalline solid.

Instead of Septomyxa, species of other genera such as Corynebacterium,Didymella, Calonectria, Alternaria, Colletotrichum, Cylindrocarpon,Ophiobolus, Fusarium, Listeria, Erysipelothrix, Mycobacterium,Tricothecium, Leptosphaeria, Curcurbitaria, Nocardia, and enzymes offungi of the family Tuberculariaceae can be used to introduce a ti -bondinto 18,20/3-epoxy-4-pregnene-3,11- dione using fermentation conditionsknown in the art.

EXAMPLE 26.1ltd-HYDROXYJSBOB-EPOXY- l,4PREGNADIENE-3-ONE Astoichiometric equivalent amount of 18,20,8-epoxy-11,B-hydroxy-4-pregnen-3-one (XIX) is substituted as starting materialfor 18,20B-ep0xy-4-pregnen-3,1l-dione in the procedure of Example 25 toobtain llB-hydroxy- 18,20fi-epoxy-1,4-pregnadien-3-one, a light coloredcrystalline solid.

EXAMPLE 27.11B,18;18,20l3-DIEPOXY- 1,4-PREGNADIEN-30NE A stoichiometricequivalent amount of 1lfi,18;l8,20 3- diepoxy-4-pregnen-3-one (XIV) issubstituted as starting material for l8,20B-epoxy-4-pregnene-3,1l-dionein the procedure of Example 25 to obtain1l{3,l8;18,20B-diepoxy-1,4-pregnadien-3-one, a light colored c1ystallinesolid.

In the same manner substituting 11fl,l8;18,20a-diepoxy- 4-pregnene-3-oneas starting material is productive of116,l8;l8,20a-diepoxy-4-pregnene-3-one.

In the same manner substituting the corresponding 21- hydroxy compoundsrepresented by Formulae VII, XIV and XIX, i.e.,18,20,8-epoxy-21-hydroxy-4-pregnene-3,11- dione,115,2l-dihydroxy-18,2013-epoxy-4-pregnen-3 one,1118,18;18,20,8-diepoxy-21-hydroxy-4-pregnen 3 one, or the correspondingZOa-epimers thereof, for 18,20fi-epoxy- 4-pregnene-3,11-dione in theprocedures of Example 25 is productive of the corresponding l-dehydrocompounds, i.e., 18,205-epoxy-21-hydroxy-1,4-pregnadiene-3,1 l-dione,1lfi,2l-dihydroxy-l8,20;8-epoxy-1,4-pregnadien 3 one, and11,8,18;l8,20,8-diepoxy-2l-hydroxy-1,4-pregnadien 3- one, respectively,and the cor-responding 20a-epimers thereof. The l-dehydro-Zl-hydroxycompounds thus produced can be acylated in accordance with the procedureof Example 7 to produce the corresponding 21-acylates of the abovelisted l-dehydro-Zl-hydroxy compounds wherein the acyl radical is thatof an acid listed in the third paragraph of Example 3.

We claim:

1. An 11,8,18 ;18,20-diepoxy compound of the pregnane series having theformula:

wherein R is selected from the group consisting of hydrogen, hydroxy and()Ac in which Ac is the acyl radical of a hydrocarbon carboxylic acidcontaining from 1 to 12 carbon atoms, inclusive, the 1,2-carbon atomlinkage is selected from the linkages consisting of single bond anddouble bond linkages and the configuration of the carbon to oxygenlinkage at the 20-position is selected from the group consisting of therat-configuration and the ,B-configuration.

2. 11/3,18;18,20B-diepoxy-4-pregnen-3-one.

3. 11B,18;18,20a-diepoxy-4-pregnen-3-one.

4. 1 113,18 ;18 ,ZOB-diepoxy- 1 ,4-pregnadien-3-one.

5. 115,18 ;18,20a-diepoxy-21-hydroxy-4pregnen3-one.

6. An 1lB,18;18,20-diepoxy compound of the pregnane series having theformula:

CHzR EEIH Cid-H 0 CHzR O H CH l/\l l CH1 I RIIIO wherein theconfiguration of the carbon to oxygen link age at the -position isselected from the group consisting of the a-configuration and theB-configuration; R is selected from the group consisting of hydrogen,hydroxy and ()Ac in which Ac is the acyl radical of a hydrocarboncarboxylic acid containing from 1 to 12 carbon atoms, inclusive; and Ris selected from the group consisting of hydrogen and Ac in which Ac isdefined as above; wherein when R' is hydrogen, R is limited to hydroxyand hydrogen and when R is Ac, R is limited to OAc and hydrogen.

8. An 11,8,18;18,20-diep0xy compound of the pregnane series having theformula:

sising of the tat-configuration and the ii-configuration; R is selectedfrom the group consisting of hydrogen, hydroxy and OAc in which Ac isthe acyl radical of a hydrocarbon carboxylic acid containing from 1 to12 carbon atoms, inclusive, and R is selected from the group consistingof hydrogen and Ac in which Ac is defined as above; wherein when R" ishydrogen, R is limited to hydroxy and hydrogen and when R is Ac, R islimited to 0A0 and hydrogen.

9. 115,1838,20B-diepoxy-5B-pregnan-3-onc.

10. 113,18;18,2OB-diepoxy-Sfi-pregnan-Ba-ol.

11. l1(3,18;18,20a-diepoxy-5fl-pregnan-3u-ol.

12. 11,8,18;18,20a-diepoxy-5fi-pregnane-F;0:,21-di0l.

13. 11fl,18;l8,20fl-diepoxy 5,8 pregnan-3a-ol 3-ace- 14.4fi-chloro-11B,18;18,2013-diepoxy 5p pregnane- 3-one.

15. A process for the production of an 11/8,18;18,20- diepoxy compoundof the formula:

0 CHzR O H C JH U OH:

AOO

wherein Ac is the acyl radical of an organic carboxylic acid; R' isselected from the group consisting of hydrogen and 0A0 in which Ac hasthe same meaning as previously given; and the configuration of thecarbon to oxygen linkage at the 20-position is selected from the groupconsisting of the tat-configuration and the fi-configuration, whichcomprises: subjecting a compound of the formula:

wherein Ac, R and the configuration of the carbon to oxygen linkage atthe 20-position are defined as above, to epoxidation with leadtetraacetate to produce the corresponding 1lfi,18;18,20-diepoxycompound. 7

16. A process for the production of an 11p,18;18,20- diepoxy compound ofthe formula:

0 CH R' OCH OH wherein Ac is the acyl radical of an organic carboxylicacid, and R is selected from the group consisting of hydrogen and OAc inwhich Ac has the meaning previously given; and the configuration of thecarbon to oxygen linkage at the 20-position is selected from the groupconsisting of the a-configuration and the B-configuration, whichcomprises; subjecting a compound of the formula:

HO clHgR CH3 OH AcO H wherein Ac and R are defined as above, todiepoxidation with lead tetraacetate to produce the corresponding 11/3,l8;l8,20-diepoxy compound.

17. A process for the production of an llfi,l8;l8,20-diepoxy-4-pregnen-3-one of the formula:

gen, hydroxy, and OAc in which Ac is the acyl radical of an organiccarboxylic acid; and the configuration of the carbon to oxygen linkageat the 20-position is selected from the group consisting of theint-configuration and the [ER-configuration, which compriseshalogenating an 11,8,18; 18,ZO-diepoxy--pregnan-3-one of the formula:

CHl jj wherein R is selected from the group consisting of hydrogen,hydroxy and OAc in which Ac is the acyl radical of an organic carboxylicacid; and the configuration of the carbon to oxygen linkage at the20-position is selected from the group consisting of therat-configuration and the B-configuration, which comprises: brominatingan 1113,18; 18,20-diepoxy-5a-pregnan-3-one of the formula:

0 CHgR O H H wherein R and the configuration of the carbon to oxygenlinkage at the 20-positi0n are defined as above, to produce thecorresponding Za,4a-dibromo-l-l,6,l8;l8,20-diepoxy- Sa-pregnan-S-Qne,dehydrohalogenating the said 2a,4a-di brorno compound with sodium iodideto produce the corresponding 2lZ-lOdO-11,8,18;18,20-diepoxy-4-pregnen-3-one and deiodinating the said Za-iOdOcompound to produce the corresponding 115,18;l8,20-diepoxy-4-pregnen-3-one.

19'. A process for the production of an 1lfl,18;18,20-epoxy-4-pregnen-3-one of the formula:

0 CHQR O H H wherein R is selected from the group consisting ofhydrogen, hydroxy, and OAc in which Ac is the acyl radical of an organiccarboxylic acid; and the configuration of the carbon to oxygen linkageat the 20-position is selected from the group consisting of theOL-COIlfigUI'ZitlOn and the fi-configuration, which comprises:subjecting an llfi-hydroxy-l8,20-epoxy-4-pregnen-3-one 3-alkylene ketalof the formula:

0 CHzR' can a lj I wherein R is selected from the group consisting ofhydrogen and OAc in which Ac is defined as above; Z is an alkyleneradical containing from 2 to 8 carbon atoms, inclusive, and having from2 to 3 carbon atoms, inclusive, in the chain connecting the oxygenatoms; and the configuration of the carbon to oxygen linkage at the20-position is defined as above, to epoxidation with lead tetraacetateto produce the corresponding l l 3,18;l8,'20-diepoxy-4-pregnen-3-one3-alkylene ketal, hydrolyzing the said ll,B,l8;l8,20-diepoxy 3-alkyleneketal thus obtained in the presence of an acid to produce thecorresponding 1l5,18;18,20 diepoxy-4-pregnen-3-one and hydrolyzing the2l-acylates thus obtained in the presence of base to produce thecorresponding 2l-free alcohols.

27 20, A process for the production of an 11,6,18;18,20-diepoxy-4-pregnen-3-one of the formula:

HO omn' CH3 H wherein R is selected from the group consisting ofhydrogen and OAc in which Ac is defined as above; and Z is an alkyleneradical containing from 2 to 8 carbon atoms, inclusive, and having from2 to 3 carbon atoms, inclusive, in the chain connecting the oxygenatoms, to diepoxidation with lead tetraacetate to produce thecorresponding 11B, 18;18,20-diepoxy-4-pregnen-3-one 3-alkylene ketal,hydrolyzing the said 1-1fl,18;18,20-diepoxy 3-a1kylene ketal thusobtained in the presence of an acid to produce the corresponding 11B,18;18,20-diepoxy-4-pregnen-3-one and hydrolyzing the 21-acylates thusobtained in the presence of a base to produce the corresponding ZI-freealcohols.

28 21. A process for the production of an 11[3,18:18,20-diepoxy-1,4-pregnadien-3-one of the formula:

0 CHzR OCH H wherein R is selected from the group consisting ofhydrogen, hydroxy and OAc in Which Ac is the acyl radical of an organiccarboxylic acid, and the configuration of the carbon to oxygen linkageat the 20-position is selected from the group consisting of thetat-configuration and the fl-configuration, which comprises: subjectingan 116,18; 18,20-diepoxy-4-pregnen-3-one of the formula:

0 CHZR O H CH wherein R and the configuration of the carbon to oxygenlinkage at the 20-position are defined as above, to l-dehydrogenation toproduce the corresponding 11 3,l8;18,20- diepoxy-l,4-pregnadien-3-one.

References Cited by the Examiner UNITED STATES PATENTS 4/63 Wettstein eta1 260-397.45

OTHER REFERENCES Heusler et al., Helv. Chim. Acta., vol. XLV, No. 39,February 1, 1962, pp. 347-350.

Kelly et al., Biochemistry, vol. 1, No. -1, January 1962, pp. 172181.

Schmidlin et al., Helv. Chim. Acta., vol. XLV, No. 38, February 1, 1962,pp. 331-347.

LEWIS GOTTS, Primary Examiner.

1. AN 11B,18;18,20-DIEPOXY COMPOUND OF THE PREGNANE SERIES HAVING THEFORMULA: